The long range objective of our laboratory is to understand the cellular and molecular mechanisms by which signaling pathways and downstream transcription factors coordinate the specification of adrenocortical cells within the adrenal gland in health and disease. Our strategy for this proposal is to focus on the mechanism and consequences of Wnt-mediated activation of gene expression in adrenal cancer. Based on our preliminary data, we hypothesize that dysregulated Wnt/?-catenin signaling in adrenocortical subcapsular cells induces aberrant target gene activation by the nuclear receptor, steroidogenic factor 1 (SF1), and ultimate oncogenic transformation of cells within this population. Our specific aims are therefore directed towards a systematic characterization of the mechanisms by which Wnt/?-catenin target genes control the normal and dysregulated growth and differentiation of the adrenal cortex. To that end we propose to determine whole genome targets of Wnt-mediated SF1 transcription in adrenocortical carcinoma (ACC) in both human patients and mice and to define the role of a subset of these target genes in adrenal cortical growth maintenance and cancer in vitro and in vivo. We believe that the studies proposed here will provide the framework for understanding the role of Wnt/?-catenin signaling in adrenocortical growth maintenance and cancer and lay the groundwork for future targeted therapy. PUBLIC HEALTH RELEVANCE: Adrenal cancer is an incredibly rare and routinely fatal disease with few effective treatments. Understanding the cellular and genetic basis for the disease is predicted to provide novel cellular and molecular targets for therapeutic intervention. This proposal aims to elucidate the mechanism and consequences of Wnt-mediated activation of gene expression in adrenal cancer. Using cellular systems and mouse models together with genomic approaches in mouse and human adrenocortical carcinoma samples, we aim to characterize the mechanisms by which Wnt/?-catenin signaling participates in normal adrenal growth maintenance and cancer. Specifically, in these studies we will determine whole genome targets of Wnt-mediated Sf1 transcription in adrenocortical carcinoma (ACC) in human patients and mice and to define the role of a subset of these target genes in both normal growth and cancer of the adrenal cortex. Future efforts are predicted to focus on therapies that target this pathway and downstream genes that are found in the course of these studies.